Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but its use is limited by dose-dependent cardiotoxicity. A recent genome-wide association study identified a SNP (rs2229774) in retinoic acid receptor-γ (RARG) as statistically associated with increased risk of anthracycline-induced cardiotoxicity. Here, we show that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with rs2229774 and who suffered doxorubicin-induced cardiotoxicity (DIC) are more sensitive to doxorubicin. We determine that the mechanism of this RARG variant effect is mediated via suppression of topoisomerase 2β (TOP2B) expression and activation of the cardioprotective extracellular regulated kinase (ERK) pathway. We use patient-specific hiPSC-CMs as a drug discovery platform, determining that the RARG agonist CD1530 attenuates DIC, and we confirm this cardioprotective effect in an established in vivo mouse model of DIC. This study provides a rationale for clinical prechemotherapy genetic screening for rs2229774 and a foundation for the clinical use of RARG agonist treatment to protect cancer patients from DIC.

阿霉素是一种蒽环类化疗药物，可有效治疗多种恶性肿瘤，但其使用受到剂量依赖性心脏毒性的限制。最近的一项全基因组关联研究发现，视黄酸受体-γ ( RARG ) 中的一个 SNP (rs2229774) 在统计学上与蒽环类药物引起的心脏毒性风险增加相关。在这里，我们表明来自 rs2229774 患者和遭受多柔比星诱导的心脏毒性 (DIC) 的人诱导多能干细胞衍生心肌细胞 (hiPSC-CM) 对多柔比星更敏感。我们确定这种RARG变异效应的机制是通过抑制拓扑异构酶 2β ( TOP2B) 心脏保护性细胞外调节激酶 (ERK) 通路的表达和激活。我们使用患者特异性 hiPSC-CM 作为药物发现平台，确定 RARG 激动剂 CD1530 减弱 DIC，并且我们在已建立的 DIC体内小鼠模型中证实了这种心脏保护作用。本研究为 rs2229774 的临床化疗前基因筛查提供了基本原理，并为临床使用 RARG 激动剂治疗以保护癌症患者免受 DIC 奠定了基础。